Thiadiazolyl amino penicillins

ABSTRACT

A PROCESS FOR THE PREPARATION OF A PENICILLIN COMPOUND OF A SALT THEREOF THE FORMULA I   2-(HOOC-),3,3-DI(CH3-),6-((4-A-1,2,5-THIADIAZOL-3-YL)-Y-   C(-B)(-X)-CO-NH-)PENAM   WHEREIN A IS HYDROGEN, ALKYL HAVING 1 TO 4 CARBON ATOMS, ARALKYL SELECTED FROM THE GROUP WHICH CONSISTS OF BENZYL AND PHENYLETHYL UNSUBSTITUTED OR SUBSTITUTED WITH CHLORO, METHOXY OR ETHOXY, OR ARYL SELECTED FROM THE GROUP WICH CONSISTS OF PHENYL AND NAPHTHYL UNSUBSTITUED OR SUBSTITUTED WITH CHLORINE, METHOXY OR ETHOXY; B IS HYDROGEN OR ALKYL HAVING 1 TO 4 CARBON ATOMS, Y IS OXYGEN OR SULFUR, X IS HYDROGEN OR ALKYL HAVING 1 TO 4 CARBON ATOMS, WHICH COMPRISES REACTING 6-AMINOPENICILLANIC ACID OR A TRIALKYLXYLYL ESTER THEREOF WITH A CARBOXYLIC ACID OF THE FORMULA II   3-(HOOC-C(-B)(-X)-Y-),4-A-1,2,5-THIADIAZOLE   OR A REACTIVE DERIVATIVE THEREOF SELECTED THE GROUP WHICH CONSISTS OF THE AZIDES, ACID CHLORIDES, ACID BROMIDES AND HYDRIDES OF SAID CARBOXYLIC ACID.

United States Patent 01 Ffice 3,816,41 l Patented June 11, 1974 1- Int.Cl. C070 99/16 US. Cl. 260239.1 4 Claims ABSTRACT OF THE DISCLOSURE Aprocess for the preparation of a penicillin compound of a salt thereofof the formula I A is hydrogen, alkyl having 1 to 4 carbon atoms,aralkyl selected from the group which consists of benzyl and phenylethylunsubstituted or substituted with chloro, methoxy or ethoxy, or arylselected from the group which consists of phenyl and naphthylunsubstituted or substituted with chlorine, methoxy or ethoxy;

B is hydrogen or alkyl having 1 to 4 carbon atoms,

Y is oxygen or sulfur,

X is hydrogen or alkyl having 1 to 4 carbon atoms, which comprisesreacting 6-aminopenicillanic acid or a trialkylxylyl ester thereof witha carboxylic acid of the formula II or a reactive derivative thereofselected from the group which consists of the azides, acid chlorides,acid bromides and anhydrides of said carboxylic acid.

The objectof the invention is a process for the preparation of newpenicillins.

It is known in the art that the N-acyl derivatives of 6-amino-penicillanic acid have an effect similar to that of naturalpenicillin (G. Erhart-H. Ruschig, Arzneimittel, 1621-1639, 2, 1968). Theantibacterial or bactericidal effect can be considerably influenced byvarying the acyl group.

It has been found that new penicillins of the general formula I A ishydrogen, alkyl, aralkyl, substituted aralkyl, aryl,

or substituted aryl,

B is hydrogen or alkyl,

Y is oxygen or sulfur,

X is hydrogen or alkyl are highly effective in inhibiting the growth ofmicroorganisms, and are very stable, which is of great advantage in oraladministration.

The term alkyl group is employed here to indicate straight or branchedalkyl groups containing preferably from 1 to 4 carbon atoms, for examplemethyl, ethyl or isopropyl groups.

When A denotes an aralkyl group, it represents advantageously a benzylor phenylethyl group.

When A stands for an aryl group, it represents preferably a phenyl ornaphthyl group.

The aralkyl or aryl groups in A position may carry one or moresubstituents, which may be halogen, preferably chlorine, or alkoxygroups, preferably methoxyor ethoxy groups.

The invention relates to novel penicillins of the general formula Iwhich are prepared by reacting 6-amino-penicillanic acid, or a salt oran ester thereof, in aqueous or anhydrous medium with a carboxylic acidof the general formula II s (II) or a reactive derivative thereof--inthe formula, A, B, X and Y have the same meaning as aboveand thepenicillins so obtained are isolated, if desired, in the form of theirsalts.

In a preferable mode of realization of the process according to theinvention one can employ the azides, halogenides (e.g. acid chlorides,acid bromides), the anhydrides, preferably mixed anhydrides of the acidsof the general formula II. The mixed anhydrides may be prepared fromcarboxylic acids and chloro-carbonic acid esters.

As G-amino-penicillanic acid ester one can employ thetrialkyl-silyl-derivatives of 6-amino-penicillanic acid, in which casethe decomposition of the acylated product is carried out in a knownmanner with water or alcohol. Acylation may be performed in the presenceor absence of carbodiimide derivatives, such as for exampledicyclohexyl-carbodiimide, diisopropyl-carbodiimide and the like.

The l,2,5-thiadiazolyl-3-O-alkane-carboxylic acids substituted in 4position, or their S-substituted derivatives, used for the preparationof the novel penicillins according to the invention, are new compounds.They may be obtained for example from the known 3-hydroxy-1,2,S-thiadiazole, 3-hydroxy-4-methyl-1,2,S-thiadiazole, or from3-hydroxy-4-phenyl-1,2,5-thiadiazole (L. M. Weinstock et al.: J. Org.Chem. 32, 2823 (1967), British Patent Specification 1,154,548).

It has been found that acids of the general formula H may be readilyprepared from 4-substituted-3-hydroxy, or 4-substituted-3-mercapto-1,2,5thiadiazoles with a-haloalkyl carboxylic acids. In the course of thesereactions one can prepare carbonxylic acids of the general formula 11.containing an asymmetrical carbon atom in a-position, if one starts fromthe corresponding a-halo-alkyl-carboxylic acids, while the antipodes maybe prepared by appropriate methods from the racemic acid. The epimericpenicillins were also prepared. We were further able to prepare theepimeric penicillins from such optically active acids as dand1-[4'-phenyl-1',2,5'-thiadiazolyl-3-O-]-a methylacetic acid.

The new penicillanic acids are preferably prepared in the form of theiralkali salts (Na, K, Ca or Mg) or of their salts formed with nontoxicorganic bases (e.g. dibenzyl-ethylene diamine, N-ethyl-pyperidine ordehydroabiethylamine.

The novel compounds according to the invention have a highly activegrowth-inhibitory effect on microorganisms. Their range of antibacterialeffect compares with 4 The method according to the invention isdescribed below more particularly in the following illustrativeExamples.

EXAMPLE 1 4.726 g. of (4-phenyl-1,2,5-thiadiazolyl-3)-oxy-acetic acid-(M.P.=l36137 C.) dissolved in dry acetone were treated at C. with 0.02moles of triethylamine. At the same temperature a solution of 2.17 g. ofchloroformic acid-ethylester in ml. of acetone were added 5=oxacillinesodium-salt 'PENICILLINS 65 acetyl]-aminopenicillanic acidpotassium-salt TABLE I Penicillin: Sensitivity to 1 2 3 4 5 oxacilStrains line Lowest inhibiting concentration in g. Notes 0. 15 0. 15 0.15 0. 15 0. 15 Agar-gel diflusion method. 0. 15 0. 15 0. 15 0. 15 0. 150. 15 0. 15 0. 15 0. 15 0. 15 0. 15 0. 15 0. 15 0. 15 0. 15 0.15 0.15 0.15 0. 15 0.15 0. 15 0. 15 0. 15 0. 15 0. 31 0.31 0. 52 0. 52 1. 2. 5 0.62 0.52 0. 52 1. 25 2. 5 0. 31 0.31 0. 31 0.31 0.52 0.31 0. 31 0. 31 0.31 0. 62

2. 5 5. 0 2. 5 2. 5 10. 0 Agar-gel difl'usion method. 5. 0 10. 0 5. 0 RR 0. 52 1. 25 1. 25 1. 25 1. 25 0. 15 0.15 0. 15 0. 15 0. 15 0. 52 1.25 1. 25 1. 25 1. 25 0.15 0. 15 0. 15 0. 15 0. 15 0. 52 1. 25 1. 25 1.25 1. 25 S 0. 31 0. 62 0. 52 0. 52 0. 52 F 2. 5 5. 0 2. 2. 50 5. 0 Str.virid 7 R 5. 0 10. 0 5.0 40. 0 B

Streptococcus faecalia:

1972/ R 6.25 50.0 6. 25 25.0 50. 0 Dilution in tube method- B 3. 12 12.5 3. 12 12. 5 50. 0 R 6. 25 25. 0 6. 25 25. 0 50. 0 R 6. 25 50. 0 6. 2525. 0 50. 0 R R R B R 400. 0 R 6. 25 12. 5 6. 25 25. 0 50. 0 R R R R B800. 0 R 3. 12 6. 25 6. 25 12. 5 50. 0 R 6. 25 25. 0 6. 25 25. 0 100. 0R 3. 12 6. 25 6. 25 12. 5 100. 0

Dtplococcus pneumoniae:

Pneumo. 1 S 0.15 0.15 0.15 0. 15 0.15 Agar-gel difluslon method- Pneumo.2 S 0. 31 0. 62 0. 62 0.62 5. 0 F8 1.25 2.5 2.5 2.5 10.0 S 0. 31 0. 620. 62 0. 62 2. 5 S 0. 15 0. 31 0.31 0. 31 0. 31 S 0. 15 0. 15 0. 15 0.15 0. 62 S 0. 31 0. 62 0. 62 0. 62 1. 25 S 0. 15 0.31 0. 31 0. 31 2. 5FS 1. 25 2. 5 2. 5 5. 0 10. 0 F8 1. 25 2. 5 2. 5 2. 5 10. 0

Neisseria pharunaitidis:

2332 0 S 0. 62 1. 25 0. 52 0. 62 1. 25 Agar-gel difluslon method.

S 0. 31 0. 62 1. 25 0. 62 0. 62 S 0. 31 0. 62 1. 25 1. 25 0. 62 S 0.62 1. 25 2. 5 1. 25 1. 25 S 0. 15 0. 62 0. 62 0. 62 0. 62 F8 5. 0 10.020. 0 10. 0 20. 0 FS 1. 25 2. 5 10. 0 2. 5 10. 0 FS 2. 5 5. 0 10. 0 10.0 10. 0 FS 5. 0 10. 0 5. 0 10. 0 20. 0 FS 2. 5 5. 0 5. 0 5. 0 10- 0Subtilis, Meseuth. Genus bacillus:

0K1 007 subtilis R 12. 5 25. 0 12. 5 25. 0 100. 0 Dilution in tubemethod. 0K1 100 008 subtilis. S 100. 0 200. 0 200. 0 200. 0 1. 56 0K1101 020 subtilis. S 50. 0 3. 18 50. 0 6. 25 0. 39 0K1 101 021 subtilis.S 12. 5 3. 12 3. 12 3. 12 0. 19 1967 subtilis S 50. 0 3. 12 50. 0 3. 120. 39 1968 subtilis. S 12. 5 3. 12 6. 25 3. 12 0. 39 1969 mesenth-. B.50.0 50. 0 50. 0 100. 0 200 0 Cereus 1 S 12. 5 25. 0 12. 5 50. 0 0. 39e118 8 100.0 50. 0 100. 0 50. 0 0. 78 3664/69 subtilis R 100. 0 100. 0100. 0 100. 0 200- 0 Abbreviations employed S:sensitive; FS=fairlysensitive R=resistaut dropwise over a period of 5 minutes, the reactionmixture was stirred for 20 minutes, whereatter the temperature wasraised to 5 C.

4.32 g. of 6-amino-penicillanic acid were suspended in 15 ml. of dist.water at 0 C., and the mixture was dissolved by adding 0.02 moles oftriethylamine. The solution so obtained was added to the reactionmixture, then stirred for 1 hour in the temperature range of +10 C.,diluted with 120 ml. of water and acidified to pH=2 by adding 10 ml. of6 N hydrochloric acid. The reaction mixture was extracted with a mixtureof 50 ml. of ethylacetate and 50 ml. of diisopropylether, then with 50ml.

of ethylacetate. The organic phase was Washed with 3X 50 m1. of water,and dried over sodium sulphate. A solution of 2 g. of anhydrouspotassiumacetate in 20 ml. of anhydrous ethanol was added to theanhydrous solution. The precipitated crystals were allowed to stand fora few hours, filtrated after dilution with 50 ml. of diisopropylether,then covered with acetone. 6.05 g. of 6-N-[4'phenyl-l',2,5'-thiadiazolyl-3'-O] -acetyl amino penicillanic acidpotassium salt were obtained, with an MP. of 190 C., with decomposition.[a] +150 [c.=2, water]. Iodometric determination showed 19.6 mls. of0.01 N iodine solution for 10 mg. of the substance.

EXAMPLE 2 To a mixture of 50 ml. of dry benzene and 5 g. of 1- [4-phenyl1,2,5 thiadiazoly1-3-O-1-a-methylacetic acid, with an MP. of 104 C. and[a] =l1.5 (c.=2, in acetone) and 1 drop of pyridine a solution of 2.5ml. of thionylchloride in 10 ml. of benzene were added dropwise, in thecourse of 30 minutes, with boiling. After boiling the mixture for 30minutes, the benzene was distilled 011 at atmospheric pressure, and theresidual acidic chloride was freed from solvent in vacuo. 5.43 g. of alight yellow oil were obtained.

4.32 g. of G-amino-penicillanic acid were suspended in 60 ml. of waterat C., then dissolved by adding 3.32 g. of sodium hydrocarbonate, anddiluted with 40 ml. of acetone. The acetone solution of the acidchloride (40 ml.) was added to the sodium salt solution dropwise within5 minutes at 2 C. The pH of the solution was kept in the range of 6.5 to8 by adding some mls. of sodium hydrocarbonate. The solution was thendiluted with 50 ml. of water, extracted with 2X50 ml. of ether, andacidified with 10 ml. of 5 N phosphoric acid.

The racemic acid mixture was extracted with a mixture of 50 ml. of etherand 50 ml. of ethyl acetate, the organic phase was washed with Wateruntil free acid, then dried over sodium sulfate. 23 ml. of a solution ofK-2- ethyl-hexanoate in n acetone were added and the solution wasallowed to stand for 16 hours at 0 C. The precipitated crystals werefiltered, covered with ether and later with acetone, and dried. 4.6 g.of 6-N-[l-(4'-phenyl- 1',2',5' thiadiazolyl-3'-O-)-a-methylacetyl]-amino-penicillanic acid potassium salt were obtained, with theMP. of 205-208 C. with decomposition, [a] 132 (c.=2, in water).Iodometric determination showed a consumption of 17.7 ml. of 0.01 Niodine solution for 10 mg. of the substance.

O-)-a-methyl acetyl-aminopenicillanic acid potassium salt may beprepared as described in Example 2. M.P.

6 208-209 C., with decomposition. (c.=2 in water).

Iodometric analysis showed a consumption of 17.7 ml.

of 0.01 N iodine solution for 10 mg. of the substance.

EXAMPLE 4 One proceeds as in Examples 2 and 3 to prepare 6-N-[d,l-(4'-phenyl 1',2',5'thiadiazolyl-3'-O-)-u-methylacetyH-aminopenicillam'c acid potassiumsalt.

M.P.: l93194 C. (with decomposition).

(c.=2, in water).

Iodometric analysis showed a consumption of 18.3 ml. of 0.01 N iodinesolution for 10 mg. of the substance.

What We claim is: 1. A compound of the formula References Cited UNITEDSTATES PATENTS 3,322,749 5/1967 Crast 260239.1 3,296,250 1/ 1967 Fraser260239.1 3,481,922 12/1969 Holdege 260239.1 3,502,655 3/1970 Oppinger260-2391 NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R. 424-271

